Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

A Nicolas, KP Kenna, AE Renton, N Ticozzi, F Faghri, R Chia, JA Dominov, BJ Kenna, MA Nalls, P Keagle, AM Rivera, W van Rheenen, NA Murphy, JJFA van Vugt, JT Geiger, RA Van der Spek, HA Pliner, Shankaracharya [No Value], BN Smith, G MarangiSD Topp, Y Abramzon, AS Gkazi, JD Eicher, A Kenna, ITALSGEN Consortium, G Mora, A Calvo, L Mazzini, N Riva, J Mandrioli, C Caponnetto, S Battistini, P Volanti, V La Bella, FL Conforti, G Borghero, S Messina, IL Simone, F Trojsi, F Salvi, FO Logullo, S D'Alfonso, L Corrado, M Capasso, L Ferrucci, Genomic Translation for ALS Care (GTAC) Consortium, CAM Moreno, S Kamalakaran, DB Goldstein, ALS Sequencing Consortium, AD Gitler, T Harris, RM Myers, NYGC ALS Consortium, H Phatnani, RL Musunuri, US Evani, A Abhyankar, MC Zody, Answer ALS Foundation, J Kaye, S Finkbeiner, SK Wyman, A LeNail, L Lima, E Fraenkel, CN Svendsen, LM Thompson, JE Van Eyk, JD Berry, TM Miller, SJ Kolb, M Cudkowicz, E Baxi, Clinical Research in ALS, Related Disorders for Therapeutic Development (CReATe) Consortium, M Benatar, JP Taylor, E Rampersaud, G Wu, J Wuu, SLAGEN Consortium, G Lauria, F Verde, I Fogh, C Tiloca, GP Comi, G Sorarù, C Cereda, French ALS Consortium, P Corcia, H Laaksovirta, L Myllykangas, L Jansson, M Valori, J Ealing, H Hamdalla, S Rollinson, S Pickering-Brown, RW Orrell, KC Sidle, A Malaspina, J Hardy, AB Singleton, JO Johnson, S Arepalli, PC Sapp, D McKenna-Yasek, M Polak, S Asress, S Al-Sarraj, A King, C Troakes, C Vance, J de Belleroche, F Baas, ALMA Ten Asbroek, JL Muñoz-Blanco, DG Hernandez, J Ding, JR Gibbs, SW Scholz, MK Floeter, RH Campbell, F Landi, R Bowser, SM Pulst, JM Ravits, DJL MacGowan, J Kirby, EP Pioro, R Pamphlett, J Broach, G Gerhard, TL Dunckley, CB Brady, NW Kowall, JC Troncoso, I Le Ber, K Mouzat, S Lumbroso, TD Heiman-Patterson, F Kamel, L Van Den Bosch, RH Baloh, TM Strom, T Meitinger, A Shatunov, KR Van Eijk, M de Carvalho, M Kooyman, B Middelkoop, M Moisse, RL McLaughlin, MA Van Es, M Weber, KB Boylan, M Van Blitterswijk, R Rademakers, KE Morrison, AN Basak, JS Mora, VE Drory, PJ Shaw, MR Turner, K Talbot, O Hardiman, KL Williams, JA Fifita, GA Nicholson, IP Blair, GA Rouleau, J Esteban-Pérez, A García-Redondo, A Al-Chalabi, Project MinE ALS Sequencing Consortium, E Rogaeva, L Zinman, LW Ostrow, NJ Maragakis, JD Rothstein, Z Simmons, J Cooper-Knock, A Brice, SA Goutman, EL Feldman, SB Gibson, F Taroni, A Ratti, C Gellera, P Van Damme, W Robberecht, P Fratta, M Sabatelli, C Lunetta, AC Ludolph, PM Andersen, JH Weishaupt, W Camu, JQ Trojanowski, VM Van Deerlin, Jr Brown RH, LH van den Berg, JH Veldink, MB Harms, JD Glass, DJ Stone, P Tienari, V Silani, A Chiò, CE Shaw, BJ Traynor, JE Landers

Research output: Contribution to journalArticle

Abstract

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS. Using a large-scale genome-wide association study and exome sequencing, we identified KIF5A as a novel gene associated with ALS. Our data broaden the phenotype resulting from mutations in KIF5A and highlight the importance of cytoskeletal defects in the pathogenesis of ALS. © 2018 Elsevier Inc.
Original languageEnglish
Pages (from-to)1268-1283.e6
JournalNeuron
Volume97
Issue number6
DOIs
Publication statusPublished - 2018

Fingerprint Dive into the research topics of 'Genome-wide Analyses Identify KIF5A as a Novel ALS Gene'. Together they form a unique fingerprint.

  • Cite this

    Nicolas, A., Kenna, KP., Renton, AE., Ticozzi, N., Faghri, F., Chia, R., Dominov, JA., Kenna, BJ., Nalls, MA., Keagle, P., Rivera, AM., van Rheenen, W., Murphy, NA., van Vugt, JJFA., Geiger, JT., Van der Spek, RA., Pliner, HA., [No Value], S., Smith, BN., ... Landers, JE. (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6. https://doi.org/10.1016/j.neuron.2018.02.027